CN101544591B - (E)-substituted styrene compound and preparation method thereof - Google Patents
(E)-substituted styrene compound and preparation method thereof Download PDFInfo
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- CN101544591B CN101544591B CN 200910074293 CN200910074293A CN101544591B CN 101544591 B CN101544591 B CN 101544591B CN 200910074293 CN200910074293 CN 200910074293 CN 200910074293 A CN200910074293 A CN 200910074293A CN 101544591 B CN101544591 B CN 101544591B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 214
- -1 (E)-substituted styrene compound Chemical class 0.000 title claims abstract description 84
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 167
- 238000006243 chemical reaction Methods 0.000 claims description 152
- 238000012544 monitoring process Methods 0.000 claims description 137
- 239000000047 product Substances 0.000 claims description 124
- 238000003756 stirring Methods 0.000 claims description 116
- 238000001035 drying Methods 0.000 claims description 101
- 238000005406 washing Methods 0.000 claims description 97
- 239000000203 mixture Substances 0.000 claims description 92
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 90
- 238000000967 suction filtration Methods 0.000 claims description 88
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 86
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 72
- 238000010025 steaming Methods 0.000 claims description 63
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 238000010992 reflux Methods 0.000 claims description 53
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 48
- 238000001816 cooling Methods 0.000 claims description 48
- 239000012044 organic layer Substances 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 43
- 230000000630 rising effect Effects 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 40
- 238000010438 heat treatment Methods 0.000 claims description 35
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 35
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 28
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 28
- 238000001953 recrystallisation Methods 0.000 claims description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 26
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 26
- 239000007864 aqueous solution Substances 0.000 claims description 24
- 238000004440 column chromatography Methods 0.000 claims description 24
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 24
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 24
- 229920006395 saturated elastomer Polymers 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 23
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 23
- 229940074386 skatole Drugs 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 18
- 239000012265 solid product Substances 0.000 claims description 16
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 239000012065 filter cake Substances 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 229950011260 betanaphthol Drugs 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 235000014493 Crataegus Nutrition 0.000 claims description 8
- 241001092040 Crataegus Species 0.000 claims description 8
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- UYEMGAFJOZZIFP-UHFFFAOYSA-N 3,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC(O)=C1 UYEMGAFJOZZIFP-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 abstract description 2
- 230000029936 alkylation Effects 0.000 abstract description 2
- 238000005804 alkylation reaction Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- 238000006722 reduction reaction Methods 0.000 abstract description 2
- 230000011987 methylation Effects 0.000 abstract 1
- 238000007069 methylation reaction Methods 0.000 abstract 1
- 238000009835 boiling Methods 0.000 description 29
- 0 COc1cc(OC)cc(*)c1 Chemical compound COc1cc(OC)cc(*)c1 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YXUIOVUOFQKWDM-UHFFFAOYSA-N COC(c1cc(OC)cc(OC)c1)=O Chemical compound COC(c1cc(OC)cc(OC)c1)=O YXUIOVUOFQKWDM-UHFFFAOYSA-N 0.000 description 2
- YIQGLTKAOHRZOL-UHFFFAOYSA-N COc1c(C=O)c2ccccc2cc1 Chemical compound COc1c(C=O)c2ccccc2cc1 YIQGLTKAOHRZOL-UHFFFAOYSA-N 0.000 description 2
- AUDBREYGQOXIFT-UHFFFAOYSA-N COc1cc(OC)cc(CO)c1 Chemical compound COc1cc(OC)cc(CO)c1 AUDBREYGQOXIFT-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- 240000001606 Adenanthera pavonina Species 0.000 description 1
- 235000011470 Adenanthera pavonina Nutrition 0.000 description 1
- LREJCUIWXQVDAX-CSKARUKUSA-N COc1cc(OC)cc(/C=C/c(c(cccc2)c2cc2)c2OC)c1 Chemical compound COc1cc(OC)cc(/C=C/c(c(cccc2)c2cc2)c2OC)c1 LREJCUIWXQVDAX-CSKARUKUSA-N 0.000 description 1
- ZKEUDGUIBVYHBZ-FNORWQNLSA-N Oc1cc(/C=C/c(c(cccc2)c2cc2)c2O)cc(O)c1 Chemical compound Oc1cc(/C=C/c(c(cccc2)c2cc2)c2O)cc(O)c1 ZKEUDGUIBVYHBZ-FNORWQNLSA-N 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 235000018991 trans-resveratrol Nutrition 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an (E)-substituted styrene compound and a preparation method thereof. The compound has potential medicinal uses, the preparation method has mild conditions and simple operations, and the compound is synthesized by the steps of performing methylation, alkylation, reduction, Wittig-Horner condensation and de-protection on 3,5-dihydroxy benzoic acid and the like.
Description
Technical field
The present invention relates to a kind of compound and preparation method thereof, specifically (E)-substituted styrene compound and preparation method thereof.
Background technology
(E)-in the substituted styrene compound representative trans-resveratrol, red sandalwood Stilbene etc. be proved to be have germ resistance, multiple pharmacologically active such as antitumor, anti-oxidant, reducing blood-fat, therefore this this compounds has caused the extensive concern of pharmaceutical companies, it is the compound that a class has the drug development prospect, how preparing this compounds and develop its medical use, is the problem that pharmaceuticals endeavours to study.
Summary of the invention
The technical issues that need to address of the present invention provide a kind of (E)-substituted styrene compound, and this compounds has potential medicinal use; The present invention also provides the preparation method of above-claimed cpd, this preparation method's mild condition, simple to operate, by 3,5-resorcylic acid by methylate, steps such as alkylation, reduction, Wittig-Horner condensation, deprotection are synthetic.
It is to realize by following technical scheme that the present invention will solve above-mentioned technical problem:
(E)-and substituted styrene compound, its structure is suc as formula (I):
R wherein
1Methyl, hydrogen or 3,5-bis trifluoromethyl benzoyl that expression replaces;
R
2Methyl, hydrogen or 3,5-bis trifluoromethyl benzoyl that expression replaces;
R
3Expression replaces or unsubstituted sec.-propyl;
R
41-skatole, 2-methoxyl group naphthyl, 2 hydroxy naphthalene, 4-(3,5-bis trifluoromethyl benzoyloxy) phenyl that expression replaces.
The present invention also provides the preparation method of above-mentioned (E)-substituted styrene compound.
As a kind of restriction of described preparation method, R in the formula (I)
1, R
2Be methyl, R
3For not replacing R
4Be the 1-skatole; Described compound is (E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy benzene) ethene, its synthetic route is as follows:
Its preparation method carries out according to following step order:
A1 3, the preparation of 5-dimethoxybenzoic acid ester A1
3,5-resorcylic acid, the mixing of Carbon Dioxide first, acetone, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 1;
B1 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B1
A1 and anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B1;
C1 3, the preparation of 5-dimethoxy benzyl chlorine C1
B1 mixes with methylene dichloride, and cooling drips SOCl in the time of-20～20 ℃
2, rise to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 1;
D1 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D1
C1, triethyl-phosphite mix, 130～170 ℃ of reflux of oil bath, the TLC monitoring, reduce pressure after reaction finishes product D 1;
E1 (E)-1-[3-(1-skatole)]-preparation of 2-(3,5-dimethoxy benzene) ethene E1
D1, tetrahydrofuran (THF) mix, and stir, and feed N
2Protection, the ice bath cooling adds NaH in the time of-20～20 ℃; stir, drip the tetrahydrofuran solution of 1-skatole-3-formaldehyde, dropwise the back temperature rising reflux; the TLC monitoring; react the Hou Jiashui that finishes, ethyl acetate extraction, washing; dry; suction filtration, revolve steam faint yellow viscous liquid, get product E 1 through column chromatography.
Another kind as the preparation method limits, R in the described formula (I)
1, R
2Be methyl, R
3Be sec.-propyl, R
4Be the 1-skatole; Described compound is (E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene, its synthetic route is as follows:
Its preparation method carries out according to following step order:
A2 3, the preparation of 5-dimethoxybenzoic acid ester A2
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 2;
B2 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B2
A2,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 2;
C2 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C2
B2, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, add an amount of lithium aluminum hydride, TLC tracking monitor when temperature is down to 0 ℃.After finishing, reaction drips saturated Na
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid thing C2;
D2 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D2
C2, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown fluid product D2;
E2 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E2
D2, triethyl-phosphite mix, reflux, and the TLC monitoring, decompression after reaction finishes gets product E2;
F2 (E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F2 synthetic
E2, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃; stir, drip the tetrahydrofuran solution of 1-skatole-3-formaldehyde, dropwise the back temperature rising reflux; the TLC monitoring; react the Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality; dry; suction filtration, revolve steam faint yellow viscous liquid, get product F2 through column chromatography.
As the third restriction of preparation method, R in the described formula (I)
1, R
2Be methyl, R
3For not replacing R
4Be 2-methoxyl group naphthyl; Described compound is (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene, and its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A3 3, the preparation of 5-dimethoxybenzoic acid ester A3
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 3;
B3 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B3
A3 and anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B3;
C3 3, the preparation of 5-dimethoxy benzyl chlorine C3
B3, methylene dichloride mix, and cooling drips SOCl in the time of-20～20 ℃
2, rise to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 3;
D3 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D3
C3, triethyl-phosphite mix, 130～170 ℃ of reflux of oil bath, the TLC monitoring, reduce pressure after reaction finishes product D 3;
The preparation of e3 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene E3
D3, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃; stir, drip the tetrahydrofuran solution of 2-methoxyl group-1-naphthaldehyde, dropwise the back temperature rising reflux; the TLC monitoring; react the Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality; dry; suction filtration revolves and steams to such an extent that product E 3 is (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene.
As preparation method's the 4th kind of restriction, R in the formula (I)
1, R
2Be hydrogen, R
3For not replacing R
4Be the 2 hydroxy naphthalene base; Described compound is (E)-1-(2 hydroxy naphthalene)-2-(3,5-dihydroxy-benzene) ethene, and its synthetic route is as follows:
The preparation method of this compound, carry out according to following step order:
A3 3, the preparation of 5-dimethoxybenzoic acid ester A3
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 3;
B3 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B3
A3 and anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B3;
C3 3, the preparation of 5-dimethoxy benzyl chlorine C3
B3, methylene dichloride mix, and cooling drips SOCl in the time of-20～20 ℃
2, rise to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 3;
D3 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D3
C3, triethyl-phosphite mix, 130～170 ℃ of reflux of oil bath, the TLC monitoring, reduce pressure after reaction finishes product D 3;
The preparation of e3 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene E3
D3, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃, stir, and drips the tetrahydrofuran solution of 2-methoxyl group-1-naphthaldehyde, dropwises the back temperature rising reflux, TLC monitoring, the reaction Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality, drying, suction filtration, revolve steam product E3;
The preparation of f4 (E)-1-(2 hydroxy naphthalene)-2-(3,5-dihydroxy-benzene) ethene F4
E3, pyridine hydrochloride mix, 150～230 ℃ of heating, TLC monitoring, reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product F 4.
As preparation method's the 5th kind of restriction, R in the described formula (I)
1, R
2Be methyl, R
3Be sec.-propyl, R
4Be 2-methoxyl group naphthyl; Described compound is (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene, and its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A5 3, the preparation of 5-dimethoxybenzoic acid ester A5
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 5;
B5 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B5
A5,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 5;
C5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C5
B5, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC tracking monitor drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product C5;
D5 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D5
C5, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D5;
E5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E5
D5, triethyl-phosphite mix, 130～170 ℃ of heating, and the TLC monitoring after reaction finishes, gets product E5;
The preparation of f5 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F5
E5, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃; stir, drip the tetrahydrofuran solution of 2-methoxyl group-1-naphthaldehyde, dropwise the back temperature rising reflux; the TLC monitoring; react the Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality; dry; suction filtration, revolve steam faint yellow viscous liquid, get product F 5 through column chromatography.
As preparation method's the 6th kind of restriction, R in the formula (I)
1, R
2Be hydrogen, R
3Be sec.-propyl, R
4Be 2-methoxyl group naphthyl; Described compound is (E)-1-(2-methoxynaphthalene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene, and its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A5 3, the preparation of 5-dimethoxybenzoic acid ester A5
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 5;
B5 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B5
A5,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 5;
C5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C5
B5, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC tracking monitor drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product C5;
D5 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D5
C5, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D5;
E5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E5
D5, triethyl-phosphite mix, 130～170 ℃ of reflux, and the TLC monitoring, decompression after reaction finishes gets product E5;
The preparation of f5 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F5
E5, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃, stir, drip the tetrahydrofuran solution of 2-methoxyl group-1-naphthaldehyde, dropwise the back temperature rising reflux, the TLC monitoring, react the Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality, dry, suction filtration, revolve steam faint yellow viscous liquid, get product F5 through column chromatography;
The preparation of g6 (E)-1-(2-methoxynaphthalene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene G6
F5, pyridine hydrochloride mix, 150～230 ℃ of heating, and the Hou Jiashui that finishes is reacted in the TLC monitoring, ethyl acetate extraction, washing, drying, suction filtration revolves steaming, gets product G 6 through column chromatography for separation.
As preparation method's the 7th kind of restriction, R in the described formula (I)
1, R
2Be hydrogen, R
3Be sec.-propyl, R
4Be 4-(3,5-bis trifluoromethyl benzoyloxy) phenyl; Described compound is (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene, its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A7 3, the preparation of 5-dimethoxybenzoic acid ester A7
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 7;
B7 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B7
A7,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 7;
C7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C7
B7, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product C7;
D7 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D7
C7, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D7;
E7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E7
D7, triethyl-phosphite mix, 130～170 ℃ of heating, TLC monitoring.The reaction finish reduce pressure product E7;
The preparation of f7 (E)-1-(4-anisole)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F7
E7, anhydrous tetrahydro furan mix, and stir, and feed N
2Protect, cooling adds NaH in the time of-20～20 ℃, stir, and drips aubepine, refluxes in the back of heating up after dropwising, and the Hou Jiashui that finishes is reacted in the TLC monitoring, ethyl acetate extraction, and washing, drying, suction filtration revolves steaming, gets product F7;
The preparation of g7 (E)-1-(4-hydroxybenzene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene G7
F7, pyridine hydrochloride mix, 150～230 heating, TLC monitoring, the reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product G7;
H7 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-preparation of 2-(3,5-dihydroxyl-4-isopropyl benzene) ethene H7
G7, ethyl acetate are mixed, and drip 3,5-dual-trifluoromethyl benzoyl chloride, stirring at room, and TLC monitoring, reaction finish to steam and desolventize, and column chromatography for separation gets product H7.
As preparation method's the 8th kind of restriction, R in the described formula (I)
1Be 3,5-bis trifluoromethyl benzoyl, R
2Be hydrogen, R
3Be sec.-propyl, R
4Be 4-(3,5-bis trifluoromethyl benzoyloxy) phenyl; Described compound is (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3-hydroxyl-4-sec.-propyl-5-(3,5-bis trifluoromethyl benzoyloxy) benzene] ethene, its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A7 3, the preparation of 5-dimethoxybenzoic acid ester A7
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 7;
B7 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B7
A7,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 7;
C7 3, the preparation of 5-dimethoxy-4 '-sec.-propyl methyl alcohol C7
B7, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product C7;
D7 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D7
C7, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D7;
E7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E7
D7, triethyl-phosphite mix, 130～170 ℃ of heating, TLC monitoring.React the aftertreatment that finishes, remove excessive triethyl-phosphite under reduced pressure, residuum E7;
The preparation of f7 (E)-1-(4-anisole)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F7
E7, anhydrous tetrahydro furan mix, and stir, and feed N
2Protect, cooling adds NaH in the time of-20～20 ℃, stir, and drips aubepine, refluxes in the back of heating up after dropwising, and the Hou Jiashui that finishes is reacted in the TLC monitoring, ethyl acetate extraction, and washing, drying, suction filtration revolves steaming, gets product F7;
The preparation of g7 (E)-1-(4-hydroxybenzene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene G7
F7, pyridine hydrochloride mix, 150～230 ℃ of heating, TLC monitoring, reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product G7;
K8 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3-hydroxyl-4-sec.-propyl-5-(3,5-bis trifluoromethyl benzoyloxy) benzene] preparation of ethene K8
G7, ethyl acetate are mixed, and drip 3,5-dual-trifluoromethyl benzoyl chloride, stirring at room, and TLC monitoring, reaction finish to steam and desolventize, and column chromatography for separation gets product K 8.
As preparation method's the 9th kind of restriction, R in the described formula (I)
1, R
2Be 3,5-bis trifluoromethyl benzoyl,, R
3For not replacing R
4Be 4-(3,5-bis trifluoromethyl benzoyloxy) phenyl; Described compound is (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3,5-two (3,5-bis trifluoromethyl benzoyloxy) benzene] ethene, its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A9 3, the preparation of 5-dimethoxybenzoic acid ester A9
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 9;
B9 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B9
A9, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B9;
C9 3, the preparation of 5-dimethoxy benzyl bromine C9
B9, methylene dichloride mix, and cooling drips PBr in the time of-20～20 ℃
3Benzole soln, rise to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 9;
D9 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D9
C9, triethyl-phosphite mix, 130～170 ℃ of heating of oil bath, the TLC monitoring, reduce pressure after reaction finishes product D 9;
The preparation of e9 (E)-1-(4-anisole)-2-(3,5-dimethoxy benzene) ethene E9
D9, anhydrous tetrahydro furan mix, and feed N
2Protect, the ice bath cooling adds NaH below-20～20 ℃, stirs, and drips aubepine, is warming up to backflow after dropwising, and the Hou Jiashui that finishes is reacted in the TLC monitoring, ethyl acetate extraction, and washing, drying, suction filtration revolves steaming, and recrystallization gets pale brown look solid E9;
The preparation of f9 (E)-1-(4-hydroxybenzene)-2-(3,5-dihydroxy-benzene) ethene F9
E9, pyridine hydrochloride mix, 150～230 ℃ of heating, TLC monitoring, reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product F9;
G9 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3,5-two (3,5-bis trifluoromethyl benzoyloxy) benzene] ethene G9 synthetic
F9, methylene dichloride adding mix, and add triethylamine, drip 3,5-dual-trifluoromethyl benzoyl chloride, stirring at room, and the aftertreatment that finishes is reacted in the TLC monitoring, revolves the steaming desolventizing, and column chromatography for separation gets product G 9.
New compound provided by the present invention has enriched the kind of (E)-substituted styrene compound, its preparation method mild condition, simple to operate, and product has potential medicinal use.
The present invention is described in further detail below in conjunction with specific embodiment.
Embodiment
Embodiment 1
(E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy benzene) ethene and preparation method thereof
(E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy benzene) ethene, its structure as shown in the formula:
Its preparation method carries out according to following step order:
A1 3, the preparation of 5-dimethoxybenzoic acid ester A1
3,5-resorcylic acid 20.00g, Anhydrous potassium carbonate 100g, acetone 200mL join in the 500mL four-hole boiling flask, and stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, the TLC monitoring.Add water after having reacted, ethyl acetate extraction, washing, drying.Suction filtration, steaming desolventize the back recrystallization, get product A 1 20.80g.Yield 81.73%.
B1 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B1
In the 500ml four-hole boiling flask, add step gained A1 and 200mL anhydrous diethyl ether, begin to stir, feed N simultaneously
2, add an amount of lithium aluminum hydride when temperature is down to 0 ℃, the TLC monitoring.After finishing, reaction drips saturated Na
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B1 16.76g, yield 94%.
C1 3, the preparation of 5-dimethoxy benzyl chlorine C1
Last step gained B1 and methylene dichloride 170mL join in the 250mL four-hole boiling flask, and cooling drips SOCl in the time of-20～20 ℃
2(0.2mol) 15.00mL rises to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 1 15.24g, yield 76%.
D1 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D1
Last step gained C1 and triethyl-phosphite 15.43mL join in the 100mL single port bottle, 130～170 ℃ of heating of oil bath, TLC monitoring, reduce pressure after reaction finishes product D 1 16.40g, yield 84%.
E1 (E)-1-[3-(1-skatole)]-preparation of 2-(3,5-dimethoxy benzene) ethene E1
Get D1 0.3g, add in the 50mL four-hole boiling flask with tetrahydrofuran (THF) 5mL, stir, feed N
2Protection, the ice bath cooling adds NaH 0.08g in the time of-20～20 ℃, stir, and drips the tetrahydrofuran solution 5mL (containing 1-skatole-3-formaldehyde amount is 0.1g) of 1-skatole-3-formaldehyde, dropwises the back temperature rising reflux, the TLC monitoring.The reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam faint yellow viscous liquid, get product E 1 through column chromatography, 0.12g, yield 66.67%.
1HNMR(500MHz，CDCl
3)(ppm)δ：3.818(s，3H)，3.867(s，6H)，6.383(s，1H)，6.702(s，2H)，7.033～7.065(d，1H)，7.233～7.363(m，5H)，7.993～8.009(d，1H)。
Embodiment 2
(E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene and preparation method thereof
(E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene structural formula is as follows:
Synthetic route is as follows:
Its preparation method, carry out according to following step order:
A2 3, the preparation of 5-dimethoxybenzoic acid ester A2
3,5-resorcylic acid 20.00g, Anhydrous potassium carbonate 100g, acetone 200mL join in the 500mL four-hole boiling flask, and stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, the TLC monitoring.Add water after having reacted, ethyl acetate extraction, washing, drying.Suction filtration, steaming desolventize the back recrystallization, get product A 2,20.80g.Yield 81.73%.
B2 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B2
The last sulfuric acid 210mL that goes on foot gained A2 and 80% joins in the four-hole boiling flask of 500mL, is heated to backflow, begins to drip Virahol 9.30mL, the TLC monitoring.The reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 2 19.43g.Yield 85%.
C2 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C2
In the 250ml four-hole boiling flask, add step gained B2 and 200mL anhydrous diethyl ether, begin to stir, feed N simultaneously
2, add an amount of lithium aluminum hydride, TLC tracking monitor when temperature is down to 0 ℃.After finishing, reaction drips saturated Na
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product C2 18.21g, yield 94%.
D2 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D2
Last step gained C2 and methylene dichloride 180mL join in the four-hole boiling flask, stir, and the ice bath cooling, dripping thionyl chloride 9.5mL in the time of-20-10 ℃ rises to room temperature reaction after dropwising, the TLC monitoring.The reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D2 17.10g.Yield 86.50%.
E2 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E2
Last step gained D2 and triethyl-phosphite 15mL join in the 100mL single necked round bottom flask, 130～170 ℃ of heating, TLC monitoring.Decompression got product E2 after reaction finished, and weight is 24.33g, yield 98.29%.
F2 (E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F2 synthetic
Get step gained E2 0.65g, add in the 50mL four-hole boiling flask with anhydrous tetrahydro furan 5mL, stir, feed N
2Protection, cooling adds NaH 0.08g in the time of-20～20 ℃, stir, and drips the tetrahydrofuran solution 5mL (1-skatole-3-formaldehyde content is 0.1g) of 1-skatole-3-formaldehyde, dropwises the back temperature rising reflux, the TLC monitoring.The reaction Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality, drying, suction filtration, revolve steam faint yellow viscous liquid, get product F 2 0.43g, yield 68.20% through column chromatography.
Embodiment 3
(E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene and preparation method thereof
(E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene, structure as shown in the formula:
(E)-synthetic route of 1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene is as follows:
Its preparation method carries out according to following step order:
A3 3, the preparation of 5-dimethoxybenzoic acid ester A3
3,5-resorcylic acid 20.00g, Anhydrous potassium carbonate 100g, acetone 200mL join in the 500mL four-hole boiling flask, and stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, the TLC monitoring.Add water after having reacted, ethyl acetate extraction, washing, drying.Suction filtration, steaming desolventize the back recrystallization, get product A 3 20.80g.Yield 81.73%.
B3 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B3
In the 500ml four-hole boiling flask, add step gained A3 and 200mL anhydrous diethyl ether, begin to stir, feed N simultaneously
2, add an amount of lithium aluminum hydride when temperature is down to 0 ℃, the TLC monitoring.After finishing, reaction drips saturated Na
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B3 16.76g, yield 94%.
C3 3, the preparation of 5-dimethoxy benzyl chlorine C3
Last step gained B3 and methylene dichloride 170mL join in the 250mL four-hole boiling flask, and cooling drips SOCl in the time of-20-20 ℃
2(0.2mol) 15.00mL rises to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 3 15.24g, yield 76%.
D3 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D3
Last step gained C3 joins in the 100mL single port bottle with triethyl-phosphite 15.43mL, 130～170 ℃ of heating of oil bath, TLC monitoring, reduce pressure after reaction finishes product D 3 16.40g, yield 84%.
The preparation of e3 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene E3
Get step gained D3 5.00g, add in the 100mL four-hole boiling flask with anhydrous tetrahydro furan 25mL, stir, feed N
2Protection, cooling adds NaH 1.64g in the time of-20～20 ℃, stir, and drips the tetrahydrofuran solution 20mL (containing 2-methoxyl group-1-naphthaldehyde 2.00g) of 2-methoxyl group-1-naphthaldehyde, dropwises the back temperature rising reflux, the TLC monitoring.The reaction Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality, drying, suction filtration, revolve steam product E 3 2.80g, yield 81.40%.
Embodiment 4
(E)-1-(2 hydroxy naphthalene)-2-(3,5-dihydroxy-benzene) ethene and preparation method thereof
(E)-1-(2 hydroxy naphthalene)-2-(3,5-dihydroxy-benzene) ethene, structure as shown in the formula:
Its synthetic route is as follows:
(E)-and the preparation method of 1-(2 hydroxy naphthalene)-2-(3,5-dihydroxy-benzene) ethene, compare with the preparation method of embodiment 3, just behind step e3, increased following steps:
The preparation of f4 (E)-1-(2 hydroxy naphthalene)-2-(3,5-dihydroxy-benzene) ethene F4
Get e3 step gained E3 0.30g, join in the single port flask with pyridine hydrochloride 1.00g, 150～230 ℃ of heating, TLC monitoring.The reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration revolves steaming, column chromatography for separation gets product F 4 0.1g, yield 38.46%.
1H?NMR(500MHz，CDCl
3)(ppm)δ：4.896(s，2H)，7.108～7.130(q，2H)，7.168～7.172(d，2H)，7.331～7.361(t，3H)，7.432～7.462(t，2H)，7.692～7.708(d，2H)，7.764～7.795(t，4H)。
Embodiment 5
(E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene and preparation method thereof
(E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene, structure as shown in the formula:
Its synthetic route is as follows:
(E)-preparation method of 1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene carries out according to the following steps order:
A5 3, the preparation of 5-dimethoxybenzoic acid ester A5
3,5-resorcylic acid 20.00g, Anhydrous potassium carbonate 100g, acetone 200mL join in the 500mL four-hole boiling flask, and stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, the TLC monitoring.Add water after having reacted, ethyl acetate extraction, washing, drying.Suction filtration, steaming desolventize the back recrystallization, get product A 5 20.80g.Yield 81.73%.
B5 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B5
Last step gained A5 joins in the four-hole boiling flask of 500mL with 80% sulfuric acid 210mL, is heated to backflow, begins to drip Virahol 9.30mL, the TLC monitoring.The reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 5 19.43g.Yield 85%.
C5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C5
In the 250ml four-hole boiling flask, add step gained B5 and 200mL anhydrous diethyl ether, begin to stir, feed N simultaneously
2, add an amount of lithium aluminum hydride, TLC tracking monitor when temperature is down to 0 ℃.After finishing, reaction drips saturated Na
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid C5 18.21g, yield 94%.
D5 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D5
Last step gained C5 and methylene dichloride 180mL join in the four-hole boiling flask, stir, and the ice bath cooling, dripping thionyl chloride 9.5mL in the time of-20～20 ℃ rises to room temperature reaction after dropwising, the TLC monitoring.The reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D5 17.10g.Yield 86.50%.
E5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E5
Last step gained D5 joins in the 100mL single necked round bottom flask with triethyl-phosphite 15mL, 130～170 ℃ of heating, TLC monitoring.Decompression got product E5 24.33g, yield 98.29% after reaction finished.
The preparation of f5 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F5
Get step gained E5 5.00g, add in the 100mL four-hole boiling flask with anhydrous tetrahydro furan 25mL, stir, feed N
2Protection, cooling adds NaH 1.64g in the time of-20～20 ℃, stir, and drips the tetrahydrofuran solution 10mL (2-methoxyl group-1-naphthaldehyde content is 2.00g) of 2-methoxyl group-1-naphthaldehyde, dropwises the back temperature rising reflux, the TLC monitoring.The reaction Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality, drying, suction filtration, revolve steam faint yellow viscous liquid, get product F 5 through column chromatography, weight 3.1g, yield 79.49%.
1HNMR(500MHz，CDCl
3)(ppm)δ：1.505～1.520(d，6H)，3.799～3.877(m，1H)，4.000(s，6H)，4.066(s，3H)，6.949(s，2H)，7.259～7.292(d，1H)，7.378～7.396(d，2H)，7.472～7.501(t，1H)，7.591～7.621(t，1H)，7.664～7.697(d，1H)，7.868～7.925(q，2H)，8.421～8.438(d，1H)。
Embodiment 6
(E)-1-(2-methoxynaphthalene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene and preparation method thereof
(E)-1-(2-methoxynaphthalene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene, structure as shown in the formula:
Its synthetic route is as follows:
Its preparation method is compared with embodiment 5, has just increased following steps behind step f5:
The preparation of g6 (E)-1-(2-methoxynaphthalene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene G6
Get f5 step gained F5 0.30g, pyridine hydrochloride 0.96g joins in the single port flask, 150～230 ℃ of heating, TLC monitoring, react the Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration revolves steaming, gets product G 6 0.16g, yield 56.00% through column chromatography for separation.
1HNMR(500MHz，CDCl
3)(ppm)δ：1.404～1.418(d，6H)，1.553(s，3H)，3.473～3.529(m，1H)，4.853(s，2H)，6.915(s，2H)，7.406(s，1H)，7.473～7.503(t，1H)，7.574～7.603(t，1H)，7.643～7.723(q，2H)，7.932～7.948(d，1H)，8.133～8.149(d，1H)。
Embodiment 7
(E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene and preparation method thereof
(E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene, structure as shown in the formula:
This compound (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-preparation method of 2-(3,5-dihydroxyl-4-isopropyl benzene) ethene carries out according to following step order:
A7 3, the preparation of 5-dimethoxybenzoic acid ester A7
3,5-resorcylic acid 20.00g, Anhydrous potassium carbonate, acetone 200mL join in the 500mL four-hole boiling flask, and stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, the TLC monitoring.Add water after having reacted, ethyl acetate extraction, washing, drying.Suction filtration, steaming desolventize the back recrystallization, get product A 7 20.80g.Yield 81.73%.
B7 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B7
Last step gained A7 joins in the four-hole boiling flask of 500mL with 80% sulfuric acid 210mL, is heated to backflow, begins to drip Virahol 9.30mL, the TLC monitoring.The reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 7 19.43g.Yield 85%.
C7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C7
Last step gained B7 and 200mL anhydrous diethyl ether begin to stir, and feed N simultaneously
2, add an amount of lithium aluminum hydride when temperature is down to 0 ℃, the TLC monitoring.After finishing, reaction drips saturated Na
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid C7 18.21g, yield 94%.
D7 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D7
Last step gained C7, methylene dichloride 180mL joins in the four-hole boiling flask, stirs, the ice bath cooling, dripping thionyl chloride 9.5mL in the time of-20～20 ℃ rises to room temperature reaction after dropwising, the TLC monitoring.The reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D7 17.10g.Yield 86.50%.
E7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E7
Last step gained D7, triethyl-phosphite 15mL join in the 100mL single necked round bottom flask, 130～170 ℃ of heating, TLC monitoring.React the aftertreatment that finishes, remove excessive triethyl-phosphite under reduced pressure, get 24.33g residuum E7, yield 98.29%.
The preparation of f7 (E)-1-(4-anisole)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F7
Last step gained E7, anhydrous tetrahydro furan 130mL join in the 250mL four-hole boiling flask, stir, and feed N
2Protection, cooling, adding NaH 6.95g stirs in the time of-20～20 ℃, drips aubepine 8.90mL, dropwises to reflux the TLC monitoring after heating up in the back.React the Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration revolves steaming, gets product F7 18.10g, yield 81.20%.
The preparation of g7 (E)-1-(4-hydroxybenzene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene G7
Last step gained F7, pyridine hydrochloride 40.20g join in the 100mL single port flask, 150～230 ℃ of heating, TLC monitoring.The reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product G7 11.75g, yield 75.00%.
H7 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-preparation of 2-(3,5-dihydroxyl-4-isopropyl benzene) ethene H7
Get step gained G7 0.1g, join in the 50mL four-hole boiling flask with ethyl acetate 10mL, drip 3,5-dual-trifluoromethyl benzoyl chloride 0.1g, stirring at room is the TLC monitoring.Reaction finishes to steam and desolventizes, and column chromatography for separation gets product H7 0.09g, yield 47.47%.
1H?NMR(500MHz，CDCl
3)(ppm)δ：1.374～1.388(d，6H)，3.439～3.481(m，1H)，4.786(s，2H)，6.506(s，2H)，6.883～7.009(q，2H)，7.217～7.234(d，2H)，7.541～7.558(d，2H)，8.151(s，1H)，8.652(s，2H)。
Embodiment 8
(E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3-hydroxyl-4-sec.-propyl-5-(3,5-bis trifluoromethyl benzoyloxy) benzene] ethene and preparation method thereof
(E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3-hydroxyl-4-sec.-propyl-5-(3,5-bis trifluoromethyl benzoyloxy) benzene] ethene, structure as shown in the formula:
Synthetic route is as follows:
Described compound (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3-hydroxyl-4-sec.-propyl-5-(3,5-bis trifluoromethyl benzoyloxy) benzene] preparation method of ethene, compare with the preparation method of embodiment 7, difference only is: back with step k8 step of replacing h7, wherein in step g 7
K8 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3-hydroxyl-4-sec.-propyl-5-(3,5-bis trifluoromethyl benzoyl) benzene] preparation of ethene K8
Get g7 step gained G7 0.1g, ethyl acetate 10mL joins in the 50mL four-hole boiling flask, drips 3,5-dual-trifluoromethyl benzoyl chloride 0.2g, stirring at room, TLC monitoring.Reaction finishes to steam and desolventizes, and column chromatography for separation gets product K 8 0.04g, yield 21.05%.
1H?NMR(500MHz，CDCl
3)(ppm)δ：1.388～1.402(d，6H)，3.450～3.507(m，1H)，6.479(s，2H)，6.860～6.978(q，2H)，7.225～7.242(d，2H)，7.529～7.546(d，2H)，8.149～8.172(d，2H)，8.584(s，2H)，8.6712(s，2H)。
Embodiment 9
(E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3,5-two (3,5-bis trifluoromethyl benzoyloxy) benzene] ethene and preparation method thereof
(E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3,5-two (3,5-bis trifluoromethyl benzoyloxy) benzene] ethene, structure as shown in the formula:
Its synthetic route is as follows:
(E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3,5-two (3,5-bis trifluoromethyl benzoyloxy) benzene] preparation method of ethene, carry out according to following step order:
A9 3, the preparation of 5-dimethoxybenzoic acid ester A9
3,5-resorcylic acid 20.00g, Anhydrous potassium carbonate 100g, acetone 200mL join in the 500mL four-hole boiling flask, and stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, the TLC monitoring.Add water after having reacted, ethyl acetate extraction, washing, drying.Suction filtration, steaming desolventize the back recrystallization, get product A 9 20.80g.Yield 81.73%.
B9 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B9
In the 500ml four-hole boiling flask, add step gained A9 and 200mL anhydrous diethyl ether, begin to stir, feed N simultaneously
2, add an amount of lithium aluminum hydride when temperature is down to 0 ℃, the TLC monitoring.After finishing, reaction drips saturated Na
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B9 16.76g, yield 94%.
C9 3, the preparation of 5-dimethoxy benzyl bromine C9
Last step gained B9, methylene dichloride 170mL joins in the 250mL four-hole boiling flask, and cooling drips PBr in the time of-20～20 ℃
3Benzole soln 25mL (0.12mol/11.40mL) rises to room temperature reaction after dropwising, and the TLC tracking monitor reacts the aftertreatment that finishes, in reaction solution impouring frozen water, stir, tell organic layer, washing, drying is filtered, revolve steam product C 9 15.24g, yield 76%.
D9 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D9
Last step gained C9, triethyl-phosphite 15.43mL join in the 100mL single port bottle, 130～170 ℃ of heating of oil bath, TLC monitoring, reduce pressure after reaction finishes product D 9 16.40g, yield 84%.
The preparation of e9 (E)-1-(4-anisole)-2-(3,5-dimethoxy benzene) ethene E9
Last step gained D9, anhydrous tetrahydro furan 160mL joins in the four-hole boiling flask, feeds N
2Protection, the ice bath cooling adds NaH 5.95g in the time of-20～20 ℃, stir, and drips aubepine 7.60mL, is warming up to backflow after dropwising, the TLC monitoring.React the Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration revolves steaming, and recrystallization gets pale brown look solid E9 13.80g, yield 81.00%.
The preparation of f9 (E)-1-(4-hydroxybenzene)-2-(3,5-dihydroxy-benzene) ethene F9
E9 gained E9, pyridine hydrochloride 59.00g join in the 250mL single port flask, 150～230 ℃ of heating, TLC monitoring.The reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product F9.
G9 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3,5-two (3,5-bis trifluoromethyl benzoyloxy) benzene] ethene G9 synthetic
Get step gained F9 1.00g, the 10mL methylene dichloride joins in the four-hole boiling flask of 50mL, adds the 0.1mL triethylamine, drips 3,5-dual-trifluoromethyl benzoyl chloride, stirring at room, TLC monitoring.React the aftertreatment that finishes, revolve the steaming desolventizing.Column chromatography for separation gets product G 9 3.83g.Yield 92.00%.
1H?NMR(500MHz，CDCl
3)(ppm)δ：7.187(s，1H)，7.265(s，2H)，7.290(s，2H)，7.405(s，2H)，7.603～7.605(d，2H)，8.184(s，3H)，8.675(s，6H)。
Claims (9)
1. the preparation method of (E)-substituted styrene compound is characterized in that its structural formula (I):
R in the formula (I)
1, R
2Be methyl, R
3For replace, R
4Be the 1-skatole, described compound is (E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy benzene) ethene, its synthetic route is as follows:
Its preparation method carries out according to following step order:
A1 3, the preparation of 5-dimethoxybenzoic acid ester A1
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 1;
B1 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B1
A1 and anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B1;
C1 3, the preparation of 5-dimethoxy benzyl chlorine C1
B1 mixes with methylene dichloride, and cooling drips SOC1 in the time of-20～20 ℃
2, rise to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 1;
D1 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D1
C1, triethyl-phosphite mix, 130～170 ℃ of reflux of oil bath, the TLC monitoring, reduce pressure after reaction finishes product D 1;
E1 (E)-1-[3-(the 1-skatole]-preparation of 2-(3,5-dimethoxy benzene) ethene E1
D1, tetrahydrofuran (THF) mix, and stir, and feed N
2Protection, the ice bath cooling adds NaH in the time of-20～20 ℃; stir, drip the tetrahydrofuran solution of 1-skatole-3-formaldehyde, dropwise the back temperature rising reflux; the TLC monitoring; react the Hou Jiashui that finishes, ethyl acetate extraction, washing; dry; suction filtration, revolve steam faint yellow viscous liquid, get product E 1 through column chromatography.
2. the preparation method of (E)-substituted styrene compound is characterized in that its structural formula (I):
R in the formula (I)
1, R
2Be methyl, R
3Be sec.-propyl, R
4Be the 1-skatole, described compound is (E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene, its synthetic route is as follows:
Its preparation method carries out according to following step order:
A2 3, the preparation of 5-dimethoxybenzoic acid ester A2
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 2;
B2 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B2
A2,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 2;
C2 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C2
B2, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds an amount of lithium aluminum hydride, and the TLC tracking monitor drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid C2;
D2 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D2
C2, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown liquid D 2;
E2 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E2
D2, triethyl-phosphite mix, 130～170 ℃ of heating, the TLC monitoring, reduce pressure after reaction finishes product E2;
F2 (E)-1-[3-(1-skatole)]-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F2 synthetic
E2, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃; stir, drip the tetrahydrofuran solution of 1-skatole-3-formaldehyde, dropwise the back temperature rising reflux; the TLC monitoring; react the Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality; dry; suction filtration, revolve steam faint yellow viscous liquid, get product F 2 through column chromatography.
3. the preparation method of (E)-substituted styrene compound is characterized in that its structure is suc as formula (I):
R in the formula (I)
1, R
2Be methyl, R
3For replace, R
4Be 2-methoxyl group naphthyl, described compound is (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene, and its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A3 3, the preparation of 5-dimethoxybenzoic acid ester A3
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 3;
B3 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B3
A3 and anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid B3;
C3 3, the preparation of 5-dimethoxy benzyl chlorine C3
B3, methylene dichloride mix, and cooling drips SOCl in the time of-20～20 ℃
2, rise to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 3;
D3 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D3
C3, triethyl-phosphite mix, 130～170 ℃ of heating of oil bath, the TLC monitoring, reduce pressure after reaction finishes product D 3;
The preparation of e3 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy benzene) ethene E3
D3, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃, stir, and drips the tetrahydrofuran solution of 2-methoxyl group-1-naphthaldehyde, dropwises the back temperature rising reflux, TLC monitoring, the reaction Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality, drying, suction filtration, revolve steam product E 3.
4. the preparation method of (E)-substituted styrene compound is characterized in that its structure is suc as formula (I):
R in the formula (I)
1, R
2Be hydrogen, R
3For replace, R
4Be the 2 hydroxy naphthalene base, described compound is (E)-1-(2 hydroxy naphthalene)-2-(3,5-dihydroxy-benzene) ethene, and its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A3 3, the preparation of 5-dimethoxybenzoic acid ester A3
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 3;
B3 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B3
A3 and anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid B3;
C3 3, the preparation of 5-dimethoxy benzyl chlorine C3
B3, methylene dichloride mix, and cooling drips SOCl in the time of-20～20 ℃
2, rise to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 3;
D3 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D3
C3, triethyl-phosphite mix, 130～170 ℃ of reflux of oil bath, the TLC monitoring, reduce pressure after reaction finishes product D 3;
E3 (E)-1-(2-methoxynaphthalene)-preparation of 2-(3,5-dimethoxy benzene) ethene E3
D3, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃, stir, and drips the tetrahydrofuran solution of 2-methoxyl group-1-naphthaldehyde, dropwises the back temperature rising reflux, TLC monitoring, the reaction Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality, drying, suction filtration, revolve steam product E3;
The preparation of f4 (E)-1-(2 hydroxy naphthalene)-2-(3,5-dihydroxy-benzene) ethene F4
E3, pyridine hydrochloride mix, 150～230 ℃ of heating, TLC monitoring, reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product F 4.
5. the preparation method of (E)-substituted styrene compound is characterized in that its structure is suc as formula (I):
R in the formula (I)
1, R
2Be methyl, R
3Be sec.-propyl, R
4Be 2-methoxyl group naphthyl, described compound is (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene, and its synthetic route is as follows:
A5 3, the preparation of 5-dimethoxybenzoic acid ester A5
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 5;
B5 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B5
A5,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 5;
C5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C5
B5, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC tracking monitor drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid C5;
D5 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D5
C5, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D5;
E5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E5
D5, triethyl-phosphite mix, 130～170 ℃ of heating, the TLC monitoring, reduce pressure after reaction finishes product E5;
The preparation of f5 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F5
E5, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃; stir, drip the tetrahydrofuran solution of 2-methoxyl group-1-naphthaldehyde, dropwise the back temperature rising reflux; the TLC monitoring; react the Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality; dry; suction filtration, revolve steam faint yellow viscous liquid, get product F 5 through column chromatography.
6. the preparation method of (E)-substituted styrene compound is characterized in that its structure is suc as formula (I):
R in the formula (I)
1, R
2Be hydrogen, R
3Be sec.-propyl, R
4Be 2-methoxyl group naphthyl, described compound is (E)-1-(2-methoxynaphthalene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene, and its synthetic route is as follows:
A5 3, the preparation of 5-dimethoxybenzoic acid ester A5
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 5;
B5 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B5
A5,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 5;
C5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C5
B5, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC tracking monitor drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product C5;
D5 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D5
C5, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D5;
E5 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E5
D5, triethyl-phosphite mix, 130～170 ℃ of heating, the TLC monitoring, reduce pressure after reaction finishes product E5;
The preparation of f5 (E)-1-(2-methoxynaphthalene)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F5
E5, anhydrous tetrahydro furan mix, and stir, and feed N
2Protection, cooling adds NaH in the time of-20～20 ℃, stir, drip the tetrahydrofuran solution of 2-methoxyl group-1-naphthaldehyde, dropwise the back temperature rising reflux, the TLC monitoring, react the Hou Jiashui that finishes, ethyl acetate extraction is washed to neutrality, dry, suction filtration, revolve steam faint yellow viscous liquid, get product F5 through column chromatography;
The preparation of g6 (E)-1-(2-methoxynaphthalene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene G6
F5, pyridine hydrochloride mix, 150～230 ℃ of heating, and the Hou Jiashui that finishes is reacted in the TLC monitoring, ethyl acetate extraction, washing, drying, suction filtration revolves steaming, gets product G 6 through column chromatography for separation.
7. the preparation method of (E)-substituted styrene compound is characterized in that its structure is suc as formula (I):
R in the formula (I)
1, R
2Be hydrogen, R
3Be sec.-propyl, R
4Be 4-(3,5-bis trifluoromethyl benzoyloxy) phenyl, described compound is (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene, its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A7 3, the preparation of 5-dimethoxybenzoic acid ester A7
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 7;
B7 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B7
A7,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 7;
C7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C7
B7, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product C7;
D7 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D7
C7, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown product liquid D7;
E7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E7
D7, triethyl-phosphite mix, 130～170 ℃ of heating, TLC monitoring.React the aftertreatment that finishes, remove excessive triethyl-phosphite under reduced pressure, residuum E7;
The preparation of f7 (E)-1-(4-anisole)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F7
E7, anhydrous tetrahydro furan mix, and stir, and feed N
2Protect, cooling adds NaH in the time of-20～20 ℃, stir, and drips aubepine, refluxes in the back of heating up after dropwising, and the Hou Jiashui that finishes is reacted in the TLC monitoring, ethyl acetate extraction, and washing, drying, suction filtration revolves steaming, gets product F7;
The preparation of g7 (E)-1-(4-hydroxybenzene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene G7
F7, pyridine hydrochloride mix, 150～230 ℃ of heating, TLC monitoring, reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product G7;
H7 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-preparation of 2-(3,5-dihydroxy-4-isopropyl benzene) ethene H7
G7, ethyl acetate are mixed, and drip 3,5-dual-trifluoromethyl benzoyl chloride, stirring at room, and TLC monitoring, reaction finish to steam and desolventize, and column chromatography for separation gets product H7.
8. the preparation method of (E)-substituted styrene compound is characterized in that its structure is suc as formula (I):
R in the formula (I)
1Be 3,5-bis trifluoromethyl benzoyl, R
2Be hydrogen, R
3Be sec.-propyl, R
4Be 4-(3,5-bis trifluoromethyl benzoyloxy) phenyl, described compound are (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3-hydroxyl-4-sec.-propyl-5-(3,5-bis trifluoromethyl benzoyloxy) benzene] ethene, its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A7 3, the preparation of 5-dimethoxybenzoic acid ester A7
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 7;
B7 3, the preparation of 5-dimethoxy-4 '-isopropyl acid B7
A7,80% sulfuric acid mix, and are heated to backflow, begin to drip Virahol, and TLC monitoring, the reaction aftertreatment that finishes slowly in the impouring frozen water, is separated out solid with reaction solution, and suction filtration is washed till neutrality with filter cake, dry product B 7;
C7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol C7
B7, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid and produces C7;
D7 3, the preparation of 5-dimethoxy-4 '-sec.-propyl benzyl chlorine D7
C7, methylene dichloride mix, stir, the ice bath cooling, dripping thionyl chloride in the time of-20～20 ℃ rises to room temperature reaction after dropwising, TLC monitoring, the reaction Hou Jiashui that finishes tells organic layer, washing, drying, suction filtration, steam desolventize reddish-brown liquid D 7;
E7 3, the preparation of 5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E7
D7, triethyl-phosphite mix, 130～170 ℃ of heating, and the aftertreatment that finishes is reacted in the TLC monitoring, removes excessive triethyl-phosphite under reduced pressure, residuum E7;
The preparation of f7 (E)-1-(4-anisole)-2-(3,5-dimethoxy-4 '-isopropyl benzene) ethene F7
E7, anhydrous tetrahydro furan mix, and stir, and feed N
2Protect, cooling adds NaH in the time of-20～20 ℃, stir, and drips aubepine, refluxes in the back of heating up after dropwising, and the Hou Jiashui that finishes is reacted in the TLC monitoring, ethyl acetate extraction, and washing, drying, suction filtration revolves steaming, gets product F7;
The preparation of g7 (E)-1-(4-hydroxybenzene)-2-(3,5-dihydroxyl-4-isopropyl benzene) ethene G7
F7, pyridine hydrochloride mix, 150～230 ℃ of heating, TLC monitoring, reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product G7;
K8 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3-hydroxyl-4-sec.-propyl-5-(3,5-bis trifluoromethyl benzoyloxy) benzene] preparation of ethene K8
G7, ethyl acetate are mixed, and drip 3,5-dual-trifluoromethyl benzoyl chloride, stirring at room, and TLC monitoring, reaction finish to steam and desolventize, and column chromatography for separation gets product K 8.
9. the preparation method of (E)-substituted styrene compound is characterized in that its structure is suc as formula (I):
R in the formula (I)
1, R
2Be 3,5-bis trifluoromethyl benzoyl, R
3For replace, R
4Be 4-(3,5-bis trifluoromethyl benzoyloxy) phenyl, described compound is (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3,5-two (3,5-bis trifluoromethyl benzoyloxy) benzene] ethene, its synthetic route is as follows:
The preparation method of this compound carries out according to following step order:
A9 3, the preparation of 5-dimethoxybenzoic acid ester A9
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone mixing, stirring at room drips methyl-sulfate, dropwises the back temperature rising reflux, and the TLC monitoring adds water after having reacted, ethyl acetate extraction, washing, drying, suction filtration, steaming desolventizes the back recrystallization, gets product A 9;
B9 3, the preparation of 5-3,5-dimethoxybenzoic alcohol B9
A9, anhydrous diethyl ether mix, and begin to stir, and feed N simultaneously
2, when being down to 0 ℃, temperature adds lithium aluminum hydride, and the TLC monitoring drips saturated Na after reaction finishes
2SO
4The aqueous solution is told organic layer, washing, and drying is filtered, and revolves steaming, gets white solid product B9;
C9 3, the preparation of 5-dimethoxy benzyl bromine C9
B9, methylene dichloride mix, and cooling drips PBr in the time of-20～20 ℃
3Benzole soln, rise to room temperature reaction after dropwising, the TLC tracking monitor, the reaction aftertreatment that finishes in reaction solution impouring frozen water, is stirred, and tells organic layer, washing, drying is filtered, revolve steam product C 9;
D9 3, the preparation of 5-dimethoxy-benzyl diethyl phosphonate D9
C9, triethyl-phosphite mix, 130～170 ℃ of reflux of oil bath, the TLC monitoring, reduce pressure after reaction finishes product D 9;
The preparation of e9 (E)-1-(4-anisole)-2-(3,5-dimethoxy benzene) ethene E9
D9, anhydrous tetrahydro furan mix, and feed N
2Protect, the ice bath cooling adds NaH below-20～20 ℃, stirs, and drips aubepine, is warming up to backflow after dropwising, and the Hou Jiashui that finishes is reacted in the TLC monitoring, ethyl acetate extraction, and washing, drying, suction filtration revolves steaming, and recrystallization gets pale brown look solid E9;
The preparation of f9 (E)-1-(4-hydroxybenzene)-2-(3,5-dihydroxy-benzene) ethene F9
E9, pyridine hydrochloride mix, 150～230 ℃ of heating, TLC monitoring, reaction Hou Jiashui that finishes, ethyl acetate extraction, washing, drying, suction filtration, revolve steam product F9;
G9 (E)-1-[4-(3,5-bis trifluoromethyl benzoyloxy) benzene]-2-[3,5-two (3,5-bis trifluoromethyl benzoyloxy) benzene] ethene G9 synthetic
F9, methylene dichloride adding mix, and add triethylamine, drip 3,5-dual-trifluoromethyl benzoyl chloride, stirring at room, and the aftertreatment that finishes is reacted in the TLC monitoring, revolves the steaming desolventizing, and column chromatography for separation gets product G 9.
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| Further Naphthylcombretastatins. An Investigation on the Role of the Naphthalene Moiety;Ana B.S.Maya,et al.;《Journal of Medicinal Chemistry》;20041231;第48卷(第2期);556-568 * |
| Justin J.Heynekamp,et al.Substituted trans-Stilbenes, Including Analogues of the Natural Product Resveratrol, Inhibit the Human Tumor Necrosis Factor Alpha-Induced Activation of Transcription Factor Nuclear Factor KappaB.《Journal of Medicinal Chemistry》.2006,第49卷(第24期),7182-7189. |
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